Laure Rondi-Reig

Cerebellum Shapes Hippocampal Spatial Code

Cerebellar protein kinase C–dependent mechanisms process self-motion information needed for spatial representation and accurate navigation. Spatial representation is an active process that requires complex multimodal integration from a large interacting network of cortical and subcortical structures. We sought to determine the role of cerebellar protein kinase C (PKC)–dependent plasticity in spatial navigation by recording the activity of hippocampal place cells in transgenic L7PKCI mice with selective disruption of PKC-dependent plasticity at parallel fiber–Purkinje cell synapses. Place cell properties were exclusively impaired when L7PKCI mice had to rely on self-motion cues. The behavioral consequence of such a deficit is evidenced here by selectively impaired navigation capabilities during a path integration task. Together, these results suggest that cerebellar PKC-dependent mechanisms are involved in processing self-motion signals essential to the shaping of hippocampal spatial representation.

Sequential egocentric strategy is acquired as early as allocentric strategy: Parallel acquisition of these two navigation strategies.

At least two main cognitive strategies can be used to solve a complex navigation task: the allocentric or map‐based strategy and the sequential egocentric or route‐based strategy. The sequential egocentric strategy differs from a succession of independent simple egocentric responses as it requires a sequential ordering of events, possibly sharing functional similarity with episodic memory in this regard. To question the possible simultaneous encoding of sequential egocentric and allocentric strategies, we developed a paradigm in which these two strategies are spontaneously used or imposed. Our results evidenced that sequential egocentric strategy can be spontaneously acquired at the onset of the training as well as allocentric strategy. Allocentric and sequential egocentric strategies could be used together within a trial, and bidirectional shifts (between trials) were spontaneously performed during the training period by 30% of the participants. Regardless of the strategy used spontaneously during the training, all participants could execute immediate shifts to the opposite non previously used strategy when this strategy was imposed. Altogether, our findings suggest that subjects acquire different types of spatial knowledge in parallel, namely knowledge permitting allocentric navigation as well as knowledge permitting sequential egocentric navigation.

The cerebellum: a new key structure in the navigation system

Early investigations of cerebellar function focused on motor learning, in particular on eyeblink conditioning and adaptation of the vestibulo-ocular reflex, and led to the general view that cerebellar long-term depression (LTD) at parallel fiber (PF)–Purkinje cell (PC) synapses is the neural correlate of cerebellar motor learning. Thereafter, while the full complexity of cerebellar plasticities was being unraveled, cerebellar involvement in more cognitive tasks—including spatial navigation—was further investigated. However, cerebellar implication in spatial navigation remains a matter of debate because motor deficits frequently associated with cerebellar damage often prevent the dissociation between its role in spatial cognition from its implication in motor function. Here, we review recent findings from behavioral and electrophysiological analyses of cerebellar mutant mouse models, which show that the cerebellum might participate in the construction of hippocampal spatial representation map (i.e., place cells) and thereby in goal-directed navigation. These recent advances in cerebellar research point toward a model in which computation from the cerebellum could be required for spatial representation and would involve the integration of multi-source self-motion information to: (1) transform the reference frame of vestibular signals and (2) distinguish between self- and externally-generated vestibular signals. We eventually present herein anatomical and functional connectivity data supporting a cerebello-hippocampal interaction. Whilst a direct cerebello-hippocampal projection has been suggested, recent investigations rather favor a multi-synaptic pathway involving posterior parietal and retrosplenial cortices, two regions critically involved in spatial navigation.

Role of the inferior olivary complex in motor skills and motor learning in the adult rat

The inferior olivary complex of adult rats was chemically destroyed using intraperitoneal injection of 3-acetylpyridine. Animals were submitted to different motor tasks: hanging test, equilibrium test and motor co-ordination test. The different scores show that 3-acetylpyridine-treated rats had motor co-ordination and static equilibrium deficiencies, whereas their rod suspension capabilities were intact. Animals were also trained on an unrotated rod or on a rod rotating at 5, 10 or 20 r.p.m. 3-Acetylpyridine-treated rats were able to maintain their equilibrium on the unrotated rod and at 5 r.p.m. Moreover, after motor training at 5 r.p.m., rats were able to improve their motor skills and reached the same score as controls. Despite their good motor skills, animals were unable to maintain their equilibrium when rotated at 10 and 20 r.p.m. These results suggest that the inferior olivary complex is needed for motor learning involving the temporal organization of movement.

MULTIMODAL SENSORY INTEGRATION AND CONCURRENT NAVIGATION STRATEGIES FOR SPATIAL COGNITION IN REAL AND ARTIFICIAL ORGANISMS

Flexible spatial behavior requires the ability to orchestrate the interaction of multiple parallel processes. At the sensory level, multimodal inputs must be combined to produce a robust description of the spatiotemporal properties of the environment. At the action-selection level, multiple concurrent navigation policies must be dynamically weighted in order to adopt the strategy that is the most adapted to the complexity of the task. Different neural substrates mediate the processing of spatial information. Elucidating their anatomo-functional interrelations is fundamental to unravel the overall spatial memory function. Here we first address the multisensory integration issue and we review a series of experimental findings (both behavioral and electrophysiological) concerning the neural bases of spatial learning and the way the brain builds unambiguous spatial representations from incoming multisensory streams. Second, we move at the navigation strategy level and present an overview of experimental data that begin to explain the cooperation-competition between the brain areas involved in spatial navigation. Third, we introduce the spatial cognition function from a computational neuroscience and neuro-robotics viewpoint. We provide an example of neuro-computational model that focuses on the importance of combining multisensory percepts to enable a robot to acquire coherent (spatial) memories of its interaction with the environment.

T-type channel blockade impairs long-term potentiation at the parallel fiber-Purkinje cell synapse and cerebellar learning.

Significance T-type calcium channels are present in the spines of a number of principal neurons. In absence of specific antagonists, their function has been difficult to elucidate. At the cerebellar synapse between parallel fiber (PF) and Purkinje cell (PC), postsynaptic Ca2+ signaling is not the result of ionotropic glutamatergic receptor activation, while T-type CaV3.1 channels are abundantly expressed in PCs. We show that they are required for long-term potentiation but not for long-term depression at PF–PC synapses. Because plasticity at this site has long been proposed to be important for cerebellar forms of motor learning, we have checked the behavioral incidence of acute or chronic blockade of T-type channels. In this condition, we show impairment of demanding cerebellar motor learning tasks. CaV3.1 T-type channels are abundant at the cerebellar synapse between parallel fibers and Purkinje cells where they contribute to synaptic depolarization. So far, no specific physiological function has been attributed to these channels neither as charge carriers nor more specifically as Ca2+ carriers. Here we analyze their incidence on synaptic plasticity, motor behavior, and cerebellar motor learning, comparing WT animals and mice where T-type channel function has been abolished either by gene deletion or by acute pharmacological blockade. At the cellular level, we show that CaV3.1 channels are required for long-term potentiation at parallel fiber–Purkinje cell synapses. Moreover, basal simple spike discharge of the Purkinje cell in KO mice is modified. Acute or chronic T-type current blockade results in impaired motor performance in particular when a good body balance is required. Because motor behavior integrates reflexes and past memories of learned behavior, this suggests impaired learning. Indeed, subjecting the KO mice to a vestibulo-ocular reflex phase reversal test reveals impaired cerebellum-dependent motor learning. These data identify a role of low-voltage activated calcium channels in synaptic plasticity and establish a role for CaV3.1 channels in cerebellar learning.

The role of climbing and parallel fibers inputs to cerebellar cortex in navigation

DA-HAN rats with partial or total lesion of climbing (CF) and parallel fibers (PF) inputs of the cerebellum were tested in a water task. Two different protocols were used, requiring to find either a non-visible or a visible platform. These two protocols were, respectively, designed to evaluate visuo-motor guidance (visible platform) and navigation (non-visible platform). Both groups of lesioned rats presented a deficit in the non-visible platform task but not in the visible platform one. The protocol of navigation we used was a fixed start-fixed arrival procedure. Totally lesioned animals were unable to learn to orient their body toward the non-visible platform and adopted instead a circling behavior. Our results suggest a role of cerebellar inputs (climbing (CF) and PF) in navigation.

A new approach for modeling episodic memory from rodents to humans: the temporal order memory.

One of the crucial issues in actual research on memory disorders and particularly in Alzheimers disease is the development of behavioral tasks accurately testing episodic memory, a type of memory sensitive to aging and altered early during neurodegenerative disorders. Translational research allowing comparison of similar memory properties between human and rodent models is a requirement for the finding of behavioral and cognitive biomarkers as well as molecular deficits associated to the pathology. In this review, we propose that the ability to remember an ordered sequence of choices during spatial navigation could be one of the episodic memory properties shared by human and rodent models. The ability to learn the correct sequence of choices depends on the hippocampus, requires flexibility and is particularly sensitive to age-related decline in rodents as in humans. In an innovative approach, we took advantage of a well characterized rodent navigation task, the starmaze, to develop a new model of episodic allowing creating and objective experimental testing of a personal past experience without requiring verbal report which can be transferred to human.

Early detection of age-related memory deficits in individual mice

To date, no consensus has been reached concerning the age of the earliest onset of age-related cognitive deficits in rodents. Our aim was to develop a behavioral model allowing early and individual detection of age-related cognitive impairments. We tested young (3 months), middle-aged (10 months) and aged (17 months) C57Bl/6 mice in the starmaze, a task allowing precise analysis of the search pattern of mice via standardized calculation of two navigation indices. We performed mouse-per-mouse analyses and compared each mouses performance to a threshold based on young mices performances. Using this method we identified impaired mice from the age of 10 months old. Their deficits were independent of any sensorimotor dysfunctions and were associated with an alteration of the maintenance of the hippocampal CA1 late-LTP. This study develops reliable methodology for early detection of age-related memory disorders and provides evidence that memory can decline in some individuals as early as from the age of 10 months.

Transgenic mice with neuronal overexpression of bcl-2 gene present navigation disabilites in a water task

In the CNS, Bcl-2 is an antiapoptotic gene involved in the regulation of neuronal death. Transgenic mice overexpressing the human gene Bcl-2 (Hu-bcl-2 mice) showed delayed acquisition in two tasks requiring them to find a hidden platform starting from either a random or a constant starting location. The same mice were not deficient in another task requiring them to find a visible platform suggesting that the delay observed was not due to motor, visual or motivational deficits in the water. The delay observed in Hu-bcl-2 mice was more important in the random starting test in which the allocentric demand for navigation was stronger. The results suggested that allocentric navigation is particularly sensitive to abnormal CNS maturation following the overexpression of the bcl-2 gene. The specific deficits (motor learning, fear-related behavior and allocentric navigation) observed in Hu-bcl-2 mice suggest that the regulation of developmental neuronal death is crucial for multisensorial learning and emotional behavior.